Arzanene had a warm climate, and was famous for its rivers and springs, as well as its iron and lead mines. Cattle-breeding, grape cultivation and wine making were well-developed. In 298 AD, part of Arzanene was conquered by the Roman Empire, while the 387 Peace of Acilisene gave the rest of the region, except for the Aghdzn district, to the Romans as well. By 591, all of Arzanene had been annexed by the East Roman or Byzantine Empire. In the place of destroyed Tigranakert, the Romans built a new city named Martyropolis or Nprkert. During the Arab conquest of Armenia, many Arab tribes settled in Arzanene. The Armenian population remained in the mountainous parts until the Armenian Genocide in 1915.

Arzanene was later a small Arab chiefdom ("Arzan") in the 9th–10th centuries. Hamdum, an Arab chief, conquered Arzanene and Amid around 962. In 963 a sister of Hamdum whose name is not given in the original sources, governed the region for ten years. After that Arzanene was part of the Bagratuni Kingdom of Armenia. After 1045 it fell successively under Byzantine, Seljuk, Mongol and OttomanTurkish control. For many years Sasun fought the Turks; well known battles are the Sasun Resistance (1894) and Sasun resistance 1915.